Mutation-Specific and Common Phosphotyrosine Signatures of KRAS G12D and G13D Alleles

Raiha Tahir, Santosh Renuse, Savita Udainiya, Anil K. Madugundu, Jevon A. Cutler, Raja Sekhar Nirujogi, Chan Hyun Na, Yaoyu Xu, Xinyan Wu, Akhilesh Pandey

Research output: Contribution to journalArticlepeer-review

Abstract

KRAS is one of the most frequently mutated genes across all cancer subtypes. Two of the most frequent oncogenic KRAS mutations observed in patients result in glycine to aspartic acid substitution at either codon 12 (G12D) or 13 (G13D). Although the biochemical differences between these two predominant mutations are not fully understood, distinct clinical features of the resulting tumors suggest involvement of disparate signaling mechanisms. When we compared the global phosphotyrosine proteomic profiles of isogenic colorectal cancer cell lines bearing either G12D or G13D KRAS mutation, we observed both shared as well as unique signaling events induced by the two KRAS mutations. Remarkably, while the G12D mutation led to an increase in membrane proximal and adherens junction signaling, the G13D mutation led to activation of signaling molecules such as nonreceptor tyrosine kinases, MAPK kinases, and regulators of metabolic processes. The importance of one of the cell surface molecules, MPZL1, which was found to be hyperphosphorylated in G12D cells, was confirmed by cellular assays as its knockdown led to a decrease in proliferation of G12D but not G13D expressing cells. Overall, our study reveals important signaling differences across two common KRAS mutations and highlights the utility of our approach to systematically dissect subtle differences between related oncogenic mutants and potentially lead to individualized treatments.

Original languageEnglish (US)
Pages (from-to)670-683
Number of pages14
JournalJournal of proteome research
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2021

Keywords

  • KRAS
  • SILAC
  • kinase
  • mass spectrometry
  • mutation
  • oncogene
  • phosphoproteome
  • phosphorylation
  • proteome
  • receptor tyrosine kinase

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

Fingerprint Dive into the research topics of 'Mutation-Specific and Common Phosphotyrosine Signatures of KRAS G12D and G13D Alleles'. Together they form a unique fingerprint.

Cite this